US 2003/0118641 A1 describes a procedure for reducing the abuse potential of oral pharmaceutical forms which contain extractable opioids. In this procedure, resistance to active compound extraction by means of customary domestic solvents, such as isopropyl alcohol, vodka, white wine vinegar, hot water or peroxides, 0.01 HCl in diluted alcohol, should in particular be brought about. It is proposed to formulate the active compound with a matrix-forming polymer and an ion exchange material, e.g. styrene-divinylbenzene polymers, in micronized form. The ion exchange material is crucial for the function of increased resistance to active compound extraction. The matrix-forming polymer obviously serves as a structure-imparting agent for the pharmaceutical core. A long list of possible substances is specified for the matrix-forming polymers, which among many other substances also comprises polymethacrylates. Preferred matrix-forming agents are C1-C6-hydroxyalkyl-celluloses.
US 2004/0052731 A1 describes a pharmaceutical form, in particular suitable for opioid active compounds, which should contribute to the reduction of the abuse potential as a result of improper administration. It is proposed to combine a lipophilic active compound variant with a water-insoluble additive, such as, for example, a fatty acid or crosslinked water-soluble polysaccharides.
US 2005/0163856 A1 describes a therapeutic procedure for the treatment of patients suffering from pain with an oxycodone-containing pharmaceutical form having reduced abuse potential as a result of dissolution in a solvent and subsequent improper administration. To this end, the active compound should be formulated with a matrix-forming polymer selected from the group consisting of hydroxypropyl-cellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose.
WO 2006/002884 A1 describes oral administration forms safeguarded against abuse, which contain a polymer, in particular a polyalkylene oxide, having a fracture resistance of at least 500 N.
WO 2006/094083 A1 describes a pharmaceutical form having controlled venlafaxine release characteristics. For the reduction of the abuse potential by addition of ethanol, the active compound is integrated into a matrix of a gelling, crosslinked polymer, e.g. xanthan. Further hydrophobic polymers, inter alia also poly-methacrylates, can be added as additives.
WO 2006/125483 describes the use of a polymer mixture for the production of coated pharmaceutical formulations and pharmaceutical formulations with mixed polymer coatings. The polymer mixtures are intended to provide modified release profiles, tailor made for the certain therapeutically requirements of different pharmaceutical ingredients, which cannot be achieved by using standard polymers. There is no indication about ethanol resistant pharmaceutical forms. In the examples pharmaceutical forms coated with mixtures of Eudragit® NE and Eudragit® FS at ratios from 5 to 50% by weight of Eudragit® FS are described. However no talcum is used in the examples or recommended in the description at high amounts as used in the present invention. The suitable thickness of the coatings from 2-20% by weight, based on the weight of the core, is much lower than those thicknesses required for the present invention.
WO 1994/0022431 A1 describes an oral pharmaceutical preparation containing a therapeutically effective amount of morphine for administration. It consists of at least 50 individual particles with an individual particle size in the range of 0.7 to 1.4 mm. Each particle has a core containing a salt of morphine coated with a barrier layer. The barrier layer contains at least one water insoluble component selected from the group of ethyl cellulose, copolymers synthesized from acrylic or methacrylic esters and natural waxes, and a plastisizer, for providing drug release through the coating barrier layer which is substantially independent of pH in the range of 1.0 to 7.0. The resulting serum concentration of morphine obtained is at least 50% of the maximum serum concentration during at least 12 hours after the administration of a single dose of said preparation.
US 2007/053698 discloses methods of sustained release administration of opioids, including but not limited to hydromorphone and oxycodone, that exhibit improved properties with respect to co-ingestion with aqueous alcohol.
Definitions
A pH-dependent controlled release pharmaceutical composition
A pH-dependent controlled release pharmaceutical composition means a pharmaceutical composition including a pharmaceutical ingredient, which is an opioid, and which is formulated with pharmaceutically acceptable film forming polymers and optionally with other pharmaceutically acceptable excipients, where the pharmaceutical composition shows a pH-dependent controlled release of the pharmaceutical ingredient.
pH-dependent controlled release
pH-dependent controlled release of the pharmaceutical ingredient means that when the pharmaceutical composition is exposed in an in-vitro dissolution test to buffered USP media with different pH values of about 1 pH step in the range from about pH 1 to about pH 7, the amount of pharmaceutical ingredient which is released or dissolved in the medium at a certain time interval differs significantly in the media with different pH values.
Buffered USP media with different pH values are known to the person skilled in the art. USP media with different pH values may have pH values for instance of pH 1.2, pH 2.0, pH 5.8, pH 6.8 and pH 7.4. An in-vitro dissolution test may be carried out in an USP dissolution apparatus, for instance apparatus No. II (paddle), 37 ° C., dissolution agitation 100 rpm, A certain time interval may be for instance 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours or even more hours.
The dissolution rate in the media with different pH values differs significantly when tested in media with different pH values pH 1.2, 2.0, 4.5, 6.8 and 7.4.
For illustration, in contrast to the pH-dependent controlled release behaviour of the present invention a typically pH independent controlled release behaviour is shown for instance in W01994/022431A1 (s. especially p.13, table 5).
Especially the pH release behaviour of the pharmaceutical composition of the present invention is pH dependent because of its gastric resistance, which means that in an USP medium of pH 1.2 there is not more than 10% of the pharmaceutical ingredient released within 2 hours, while at higher pH values, for instance at pH 7.4, there is significantly more than 10% of the pharmaceutical ingredient released within 2 hours. In contrast the pH independent controlled release form of W01994/022431A1 (s. p. 13, table 5) may show an identical release rate of 15% after 2 hours in a pH 1.2 or pH 7.4 buffered medium.
Opioids
An opioid in the sense of the present invention means an agent that binds to an opioid receptor as found in the central nervous system or in the gastrointestinal tract of man or mammalian animals and shows a more or less strong narcotic effect (opioid agonist). In contrast to opioids, opioid antagonists, like for instance naloxone, can also bind to opioid receptors, but do not show strong narcotic effects. An opioid in the sense of the present invention comprise opioids selected from opium alkaloids, semi-synthetic opioids or wholly synthetic opioids.
Opioids in the sense of the present invention include pharmaceutically acceptable salts, free base or free acid forms of opium alkaloids, semi-synthetic or wholly synthetic opioids.
Pharmaceutically acceptable salts include, but are not limited to:                metal salts such as sodium salt, potassium salt, secium salt and the like;        alkaline earth metals such as calcium salt, magnesium salt and the like;        inorganic acid salts such as hydrochloride, hydrobromide, sulphate, phosphate and the like;        organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;        organic acid salts such as methansulfonate, benzenesulfonate, p-toluenesulfonate and the like;        amino acid salts such as arginate, asparaginate, glutamate and the like.        
Examples of opium alkaloids comprise morphine, codeine and thebaine.
Examples of semi-synthetic opioids comprise diamorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone and nicomorphine.
Examples of wholly synthetic opioids comprise methadone, levomethadyl acetate hydrochloride (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine and phenazocine.
Other opioids are known to one skilled in the art. Preferred opioids in the practice of the present invention are orally bioavailable. More preferred opioids comprise morphine, hydromorphine, hydrocodone, oxymorphone and oxycodone. Other opioids are buprenorphine, hydromorphone, levorphanol, tramadol, tilidine, sufentanil, pentozocine, nalbuphine, meptazinol, meperidine or fentanyl.
In a preferred embodiment of the present invention the pharmaceutical composition may contain only one opioid (opioid agonist) and no other active ingredients.
In another preferred embodiment of the present invention the pharmaceutical composition may contain mixtures of different opioids (opioid agonists). Preferably except from the opioid mixture no further pharmaceutical active ingredients which are not opioids may be included, especially no opioid antagonists may be contained.
In another preferred embodiment of the present invention the pharmaceutical composition may contain a mixture or a combination of one or more opioids (opioid agonists) and one or more opioid antagonists. Preferably only one combination of one opioid and one opioid antagonist may be included. Known mixtures or combinations of opioid agonists and an opioid antagonists are for instance the combinations of pentazocine and naloxone, tilidine and naloxone and morphine and naloxone (see for instance EP 1 810 678 A1 or US 2007/053698).
In another preferred embodiment of the present invention the pharmaceutical composition preferably contains a pharmaceutical active ingredient which is an opioid (opioid agonist) and, if applicable, another pharmaceutical active ingredient, which is not an opioid.
Polymer mixture
The term polymer mixture in the sense of the present invention means the mixture of                i) 40-95% by weight, based on dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer or copolymer, and        ii) 5-60% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0.        
The neutral cellulosic compound, which is also a polymer present in the coating layer, is not calculated as a part of this polymer mixture but calculated separately in relation to the dry weight of this polymer mixture. The emulsifier present in the coating layer is also calculated on basis of the dry weight of the polymer mixture compounds i) and ii) without the neutral cellulosic polymer.
Inert non-porous lubricants
The coating layer may further contain 110 to 250, preferably 140-220% by weight, calculated on dry weight of the polymer mixture, of a non-porous inert lubricant.
Lubricants (sometimes also called glidants) are pharmaceutically acceptable substances which help in preventing agglomeration of polymers during the coating process.
Porous lubricants like silica powders are not suitable for the purposes of the present invention. Porous structures may possibly cause capillary effects that promote the enhanced penetration of the coating by aqueous alcoholic respectively ethanolic media.
Inert means that the lubricant does normally not chemically interact with other substances and is not soluble or only poorly soluble in water and/or ethanol. Not soluble or only poorly soluble means more than 10 parts by weight of solvent required per 1 part by weight of solute. Furthermore inert non-porous lubricants essentially do not influence the glass transition temperature of the polymer mixture of the coating.
Lubricants like glycerol monostearate (GMS), which can not be applied in sufficient amounts to the coating layer to convey resistance against ethanol containing aqueous media are per se not suitable in the sense of the invention. Thus glycerol monostearate (GMS) is not inert in the sense of the invention.
The non-porous inert lubricant may be a layered silica component, a pigment or a stearate compound.
The inert lubricant may be Ca- or Mg-stearate. The inert lubricant may be TiO2.
Most preferred as an inert non-porous lubricant is talc.
Ethanol resistant pharmaceutical formulations
Ethanol resistant pharmaceutical formulations are formulations with release kinetics not significantly affected in the presence of ethanol. Ethanol resistance may be an important registration requirement in the near future. Conventional pharmaceutical coatings, particularly on pellets, are not sufficiently resistant to alcohol. Surprisingly it was found that coatings combining an insoluble and soluble film former provide a higher resistance to alcohol.
An ethanol resistant or sometimes also called rugged formulation is defined by comparing in-vitro release data from testing at pH 1.2 and/or pH 6.8 in alcohol free media and equivalent media containing 40% ethanol (details see attachment) and maintaining a difference in release profiles of less than 15% if the release in alcohol free media is less than 20% of the total dose and a difference of less than 30% difference, if the release of the total dose is between 20% and 80%.
Object and achievement
The present invention originates from controlled release pharmaceutical forms for oral administration. This type of pharmaceutical form is intended for more or longer-lasting release of active compound, usually during intestinal passage. It is attempted to achieve by means of appropriate formulation of the pharmaceutical form, that, after an initial increase of the concentration of the active compound in the blood level, the blood level shall remain in the therapeutically optimal range as long as possible. Especially too high blood level concentrations of the active compound, which may have toxic effects, should be avoided.
In the case of the release-delaying formulations of oral pharmaceutical forms, the influence of the gastric juice and of the intestinal juices, in particular the ionic strength and the environmental pH, is substantially to be taken into consideration in a manner known per se. A problem exists in that the ideal ratios assumed here for the release of active compound can be altered by the general living habits, thoughtlessness or by addictive behaviour of the patients with respect to the use of ethanol or ethanol-containing drinks. In these cases, the pharmaceutical form which is actually designed for an exclusively aqueous medium is additionally exposed to an ethanol containing medium of greater or lesser strength.
On account of the dissolution of oral delayed-release pharmaceutical forms in alcoholic drinks or simultaneous or overlapping taking thereof with alcoholic drinks, an undesired or even critical acceleration or slowing of the release of active compound can occur. In most cases the presence of ethanol leads to an acceleration of release of the ingredient. So acceleration is the major problem, while slowing is usually less critical. An acceleration or an addition of more than 30% of the release of the pharmaceutical active ingredient absolutely to the release in % without the presence of 40% ethanol must be considered critically.
Since not all patients are aware of the risk of simultaneous taking of a controlled release pharmaceutical form and ethanol-containing drinks or do not follow or are not able to follow appropriate warnings, advice or recommendations, the object is to design oral delayed-release pharmaceutical forms such that their mode of action is affected as little as possible by the presence of ethanol.
The pH-dependent controlled release pharmaceutical composition according to the invention may also be used to reduce the risk of abuse of the included pharmaceutical active ingredient by in-vitro extraction using ethanol containing media before oral ingestion.
The purpose of the present invention is expressively not to stimulate, to promote or to make possible the taking of ethanol-containing drinks together with delayed-release pharmaceutical forms, but to alleviate or to avoid the possibly fatal consequences of intentional or inadvertent abuse. In-vitro means that the extraction takes place out side the human body, for example by extraction of the opioid by addition of high percentage alcoholic drinks like Whiskey or Vodka to the dosage form in a glass.
Because of the not predictability of in-vivo effects, the present invention is based on in-vitro conditions as objectively comprehensible bases of measurement. As a severe test condition in-vitro conditions according to USP Method 1 (basket), 100 rpm, buffered at pH 6.8 (European Pharmacopoeia) in a medium with and without the addition of 40% (v/v) ethanol may be chosen.
One object of the invention is solved when the controlled release pharmaceutical composition fulfils the following conditions:                under conditions according to USP Method 1 (basket), 100 rpm buffered at pH 1.2 for the first two hours or pH 6.8 (European Pharmacopoeia) for the remaining time respectively where the pharmaceutical active ingredient is released to a degree of less than 20% without the addition of 40% (v/v) ethanol, the difference in the release rate with the addition of 40% (v/v) ethanol shall not be more than plus or minus 15% of the corresponding release value without 40% (v/v) ethanol. For example under conditions where the pharmaceutical active ingredient is released to a degree of 18% without the addition of 40% (v/v) ethanol, the release rate with the addition of 40% (v/v) ethanol shall not differ to more than plus or minus 15% of the release value without 40% (v/v) ethanol, which means that it may be in the range from 3 to 33%.        under conditions according to USP Method 1 (basket), 100 rpm buffered at pH 1.2 for the first two hours or pH 6.8 (European Pharmacopoeia) for the remaining time respectively where the pharmaceutical active ingredient is released to a degree of 20-80% without the addition of 40% (v/v) ethanol, the difference in the release rate with the addition of 40% (v/v) ethanol shall not be more than plus or minus 30% of the corresponding release value without 40% (v/v) ethanol. For example under conditions where the pharmaceutical active ingredient is released to a degree of 50% without the addition of 40% (v/v) ethanol, the release rate with the addition of 40% (v/v) ethanol shall not differ to more than plus or minus 30% of the release value without 40% (v/v) ethanol, which means that it may be in the range from 20 to 80%.        
A controlled release pharmaceutical composition which fulfils this condition can be considered to be resistant against critically accelerated release of the active compound by thoughtlessness or by addictive behaviour of the patients with respect to the use of ethanol or ethanol-containing drinks.
This situation relates essentially to the simultaneous or subsequent consumption of an alcoholic drink together with the taking of the controlled release pharmaceutical form, such that the pharmaceutical form is exposed to a strong ethanol-containing medium in the stomach or intestine.
One object of the present invention is to provide a pharmaceutical composition for opioids which is resistant against the influence of ethanol.
Since opioids shall be released preferably over a prolonged time period, for instance more than 12 up 16 or 24 hours, there is a need for an ethanol resistant pharmaceutical composition, where the opioid is released to a degree of 75% or less preferably to a degree of 50-75%, most preferred to a degree of 55-70%, after 12 hours in simulated gastric fluid pH 1.2 (USP) for the first 2 hours and in buffered medium pH 6.8 (USP) for the remaining time with or without the addition of 40% ethanol (v/v) in the media.
Another object is the storage stability of the pharmaceutical composition which should be further improved to be in the range of 60-100 expressed as f2-value (storage stability=good).
Measurement methods
The measurement of the percentage amount of active compound released can be carried out, for example, by on-line UV spectroscopy at a wavelength suitable for the respective active compound. HPLC determination is also possible. The methodology is familiar to a person skilled in the art.
The release of active compound can be determined according to USP, in particular USP 28-NF23, General Chapter <711>, Dissolution, Apparatus 1 (basket), Method <724>“Delayed Release (Enteric Coated) Articles-General General Drug Release Standard” correct citation needed!, Method B (100 rpm, 37° C.), type I basket, with the following modification: The pharmaceutical forms are tested at pH 1.2 for the first 2 hours using 0.1 N HCl medium or at pH 6.8 using a phosphate buffer (European Pharmacopoeia (EP)) for the remaining time, which corresponds to an artificial intestinal medium. The measurement in the ethanol containing aqueous medium is carried out using the appropriate amount of 40% ethanol (v/v) in the medium.
Storage stability
In general, drug substances should be evaluated under storage conditions (with appropriate tolerances) that test thermal stability and, if applicable, its sensitivity to moisture (ICH Guideline Q1A (R2), 6 Feb. 2003).
Accelerated conditions for drug substances: 40° C. +/−2° C., 75% RH (relative humidity) +/−5% RH, closed containers, period of 6 months. Storage stability may be expressed by the so called similarity factor f2 or f2-value. The similarity factor f2 is inversely proportional to the average squared distance between the two release profiles before and after storage. During the last decade f2 calculation has become a recommended method in several FDA guidances for Industry. The calculation process is known to the skilled person. An f2-value of 100 means that there is no deviation in the average squared distance between the two release profiles before and after storage.
The storage stability is considered to be acceptable, when the deviation of the release profile before and after storage is expressed by a similarity f2-value of 50 or more but less than 60. The storage stability is considered to be good, when the deviation of the release profile before and after storage is expressed by an f2-value of 60 to 100. Storage stability testing is well known to a person skilled in the art.